Case#: T.II.1, subject 48. Male. Age of Onset: 1.5 y.o. Age of evaluation: 21 y.o. Origin in UK, Caucasian.

*DiseaseAssertion: Cytopenia, Evans syndrome

*FamilyInfo: Father had died post autologous HSCT for non-Hodgkin lymphoma. See "supplement 1".

CasePresentingHPOs: ORPHA:1959

CaseHPOFreeText: Severe Psoriatic Arthritis (only patient noted to have it within the study), received a Hematopoietic stem cell transplantation and was one of nine affected mutation carriers still alive and one of three who was more than five years post-HSCT and currently well off all medication at the time of publication.

*CaseNotHPOs: large phenotype table with unreported symptoms in table S1

*CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: Yes, Slatter, et al. PMID: 27102614

Variant: c.518G>A, p.G173E

ClinVarID: N/A

CAID: CA350138990

gnomAD: Not Found

SupplementalData: extensive data in S1

Note: Not functionally tested using transendocytosis

Case#: Q.II.1, subject 44. Male. Age of Onset: 10 y.o. Age of evaluation/death: 15 y.o. Origin in UK, Caucasian.

DiseaseAssertion: Lymphoproliferation

FamilyInfo: Not found

CasePresentingHPOs: HP:0001744, HP:0002716, HP:0002783, HP:0000964, HP:0001873

CaseHPOFreeText: Three affected mutation carriers (including patient) died following alloHSCT due to GvHD. Patient received transplant due to having Thrombocytopenia and widespread lymphoid hyperplasia despite Rituximab. Patient died four months post transplant due to Acute GvHD Grade IV of the gut. See Table S2.

Lymphocytic or granulomatous organ infiltration - patient's brain was affected. Patient received a biopsy and was found to have B Cell and T Cell infiltration. Vaccination response - Tetanus, Pneumococcal vaccination. Respiratory tract involvement, GLILD, Cytopenia, Splenectomy, Autoimmune cytopenia, ITP, Neurological involvement, Dermatological involvement, Coombs.

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: Yes, Slatter, et al. PMID: 27102614

Variant: NM_005214.5:c.529T>G

ClinVarID: N/A

CAID: CA350139018

gnomAD: Not found

SupplementalData: extensive data in S1

Note: Not functionally tested using transendocytosis

Case#: OO.II.1, subject 95. Male. Age of Onset: 18 y.o. Age of evaluation: 24 y.o. Origin in Germany, Caucasian.

DiseaseAssertion: CVID

FamilyInfo: Patient was included in group of families who had a documented mutation at Exon: 2 and AA Position: 75. Mutations were: p.R75W (c.223C>T) and p.R75Q (c.224G>A). Family groups were: Family E, Family X, Family JJ, Family UU; Family OO.

CasePresentingHPOs: ORPHA:1572 (CVID), HP:0004313 (Hypogammaglobulinemia), HP:0004315 (Low IgG), HP:0001744 (Splenomegaly), HP:0200117 (Recurrent upper and lower respiratory tract infections), HP:0002090 (Pneumonia), HP:0002110 (Bronchiectasis), HP:0002726 (Recurrent Staphylococcus aureus infections), OMIM:188030 (Immune thrombocytopenic purpura/ITP)

CaseHPOFreeText: Respiratory involvement, Low IgM, Low IgA, Lymphoproliferation, Respiratory tract involvement, GLILD, Cytopenia, Autoimmune cytopenia

Bacterial infection: Hemophilus influenzae

Lymphocytic or granulomatous organ infiltration - Lung.

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: N/A

Variant: NM_005214.5:c.224G>A

ClinVarID: 943305

CAID: CA350138321

gnomAD: Not found

SupplementalData: extensive data in S1

Note: Functionally tested using transendocytosis

Case#: YY.II.1, subject 127. Female. Age of Onset: 3 y.o. Age of evaluation: 14 y.o. Origin in Germany, Caucasian.

DiseaseAssertion: Gastrointestinal involvement

FamilyInfo: None found

CasePresentingHPOs: HP:0001510 (Growth retardation), HP:0001744 (Splenomegaly), HP:0002240 (Hepatomegaly), HP:0002716 (Lymphadenopathy), HP:0200117 (Recurrent upper and lower respiratory tract infections), HP:0002726 (Recurrent Staphylococcus aureus infections), HP:0020114 (Persistent human papillomavirus infection/HPV), HP:0002014 (Diarrhea), HP:0002242 (Enteropathy), HP:0100280 (Crohn's disease), HP:0001047 (Atopic dermatitis), HP:0000964 (Eczema), HP:0200043 (Warts)

CaseHPOFreeText: Lymphoproliferation, Respiratory tract involvement, Dermatological involvement, Liver involvement

Lymphocytic or granulomatous organ infiltration - Liver and gut

Vaccination response - Tetanus, Diphtheria and Pneumococcal

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: N/A

Variant: NM_005214.5:c.326G>A

ClinVarID: 542071

CAID: CA2067088

gnomAD: 2:204735525 G / A

SupplementalData: extensive data in S1

Note: Functionally tested using transendocytosis

Case#: AAA.II.1, subject 130. Male. Age of Onset: 23y.o. Age of evaluation: 46 y.o. Origin in Switzerland, Caucasian.

DiseaseAssertion: Gastrointestinal involvement

FamilyInfo: None found

CasePresentingHPOs: HP:0008207 (Addison's disease), HP:0004313 (Hypogammaglobulinemia), HP:0002720 (Low IgA), HP:0002014 (Diarrhea), HP:0002242 (Enteropathy), HP:0012410 (PRCA/Pure red cell aplasia)

CaseHPOFreeText: Lymphoproliferation, Cytopenia, Autoimmune cytopenia, Endocrinological involvement, Kidney involvement

Lymphocytic or granulomatous organ infiltration of the gut

Thirty-five percent of affected mutation carriers (27/78) were under antibiotic prophylaxis. In one affected mutation carrier (the patient) treatment with vedolizumab (blocking α4β7 integrin) improved colitis, and in the same individual PRCA responded well to cyclosporine A.

IgG levels: no values were available before IVIG or Rituximab

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: Yes, Navarini et al. PMID: 27908448

Variant: NM_005214.5:c.257C>T

ClinVarID: 661941

CAID: CA2067080

gnomAD: 2:204735456 C / T

SupplementalData: extensive data in S1

Note: Functionally tested using transendocytosis

Case#: 2/M. 10 y.o. (onset) and 13 y.o. (at assessment), male

DiseaseAssertion: Patient had thrombocytopenia, associated bleeding, neutropenia, and lymphoid hyperplasia in lungs, lymph nodes, and brain, refractory to immunomodulatory therapy. The diagnosis of CTLA4 haploinsufficiency was made retrospectively in 7 patients who underwent HSCT for life-threatening, treatment-resistant immune dysregulation and in 1 patient prospectively (unclear which patients were identified retrospectively and prospectively).

FamilyInfo: None provided

CasePresentingHPOs: HP:0001873 (Thrombocytopenia), HP:0001875 (Neutropenia), OMIM:188030 (Immune thrombocytopenic purpura/ITP), HP:0001904 (Autoimmune neutropenia)

CaseHPOFreeText: ITP and autoimmune neutropenia, Reactive lymphoid hyperplasia—lymph nodes, lung, frontal lobe brain.

All 8 patients received steroids and a calcineurin inhibitor before transplant

Five patients (including this patient) had peripheral blood HSC grafts and received cyclosporine and mycophenolate mofetil (MMF) for graft versus host disease (GvHD) prophylaxis.

Patient died 4 months post-transplant due to transplant-related mortality of severe acute gut GvHD (Acute grade IV gut).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Not found

GenotypingMethod: Not found

PreviouslyPublished: Yes, Schwab et al. PMID: 29729943

Variant: NM_005214.5:c.529T>G

ClinVarID: N/A

CAID: CA350139018

gnomAD: Not found

SupplementalData: More information regarding Lymphocyte subsets and Immunoglobulins in Table I. Table II contains variant information and Table III contains further details about HSCT and a breakdown of each patient's transplant procedure.

Note: No mention of whether or not the patient was tested using transendocytosis.

Case#:1/M. 1.5 y.o. (onset) and 14 y.o. (at assessment), male

DiseaseAssertion: Patient had arthritis, neutropenia and thrombocytopenia, lymphadenopathy, and abdominal pain. The diagnosis of CTLA4 haploinsufficiency was made retrospectively in 7 patients who underwent HSCT for life-threatening, treatment-resistant immune dysregulation and in 1 patient prospectively (unclear which patients were identified retrospectively and prospectively).

FamilyInfo: Father was noted to have Immune dysregulation, Cytopenias and Lymphoma. The patient's father was also noted to have a complex autoimmune disease and died after autologous HSCT for non-Hodgkin lymphoma.

CasePresentingHPOs: HP:0001369 (Arthritis), HP:0001875 (Neutropenia), HP:0001873 (Thrombocytopenia), HP:0002716 (Lymphadenopathy), HP:0002027 (Abdominal pain), HP:0002720 (Decreased circulating IgA level).

CaseHPOFreeText: Autoimmune pancytopenia, Recurrent abdominal pain, Arthritis

This patient was offered HSCT because of ongoing autoimmunity and risk of lymphoma because his father had complex autoimmune disease and died after autologous HSCT for non-Hodgkin lymphoma.

All 8 patients received steroids and a calcineurin inhibitor before transplant

Five patients (including this patient) had peripheral blood HSC grafts and received cyclosporine and mycophenolate mofetil (MMF) for graft versus host disease (GvHD) prophylaxis.

Patient had cytomegalovirus reactivation early post-HSCT and autoimmune hemolytic anemia 6 months post-HSCT, which responded to steroids; he is now off all medication.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Patient has low levels of IgA but IgG and IgM levels appear to be within normal range. See Table I.

CasePreviousTesting: Not found

GenotypingMethod: Not found

PreviouslyPublished: Yes, Schwab et al. PMID: 29729943

Variant: c.518G>A, p.G173E

ClinVarID: N/A

CAID: CA350138990

gnomAD: Not found

SupplementalData: More information regarding Lymphocyte subsets and Immunoglobulins in Table I. Table II contains variant information and Table III contains further details about HSCT and a breakdown of each patient's transplant procedure.

Note: No mention of whether or not the patient was tested using transendocytosis.

Case#: N/A. Patient was the only one included in this paper. Male. Age of Onset: 9 y.o. Age of evaluation: 42 y.o onwards. Age of Death: ~49 y.o. Origin in Portugal, ethnicity not specified.

DiseaseAssertion: Evans Syndrome

FamilyInfo: No familial segregation analysis could be performed as the patient′s first‐degree relatives (reportedly healthy) refused genetic testing, and the patient had no progeny. Additionally, when the patient was diagnosed and treated for other health conditions, it was noted that "There was no relevant family history".

CasePresentingHPOs: ORPHA:1959 (Evan's syndrome), HP:0002014 (Diarrhea), HP:4000055 (Intestinal Inflammation), HP:0002719 (Severe/Recurrent Infections), HP:0000403 (Recurrent Otitis), HP:0002254 (Intermittent Diarrhea), HP:0001873 (Severe Thrombocytopenia), HP:0002090 (Pneumonia), HP:0004315 (low IgG), HP:0002720 (low IgA), HP:0001082 (Cholecystitis), HP:0001433 (Hepatosplenomegaly), HP:0008711 (Benign prostatic hypertrophy), HP:0012227 (urethral stricture), HP:0003508 (Proportionate Short Stature), HP:0001888 (Lymphopenia), HP:0410385 (Low levels of CD8+ T cells), HP:0410378 (Low levels of CD4+ T cells),

CaseHPOFreeText: Lymphoproliferation, mild ileal inflammatory infiltrate on histology and hemolysis, lower limb cellulitis, IgE and IgD levels were undetectable, but IgM levels were normal, Bilateral osteonecrosis of femoral head and condyles at age 43, Facial vitiligo, Hemoglobin 12.5 g/L; leukocytes: 8700/μL; platelets 28000/μL, trabeculated bladder.

Duodenal, ileal and bladder biopsy: inflammatory infiltrate (not characterized) Negative: direct Coombs, ANA, EBV DNA, CMV DNA, hepatitis B, C, HIV, proteinuria, urinary Ig loss Antiplatelet Ab positive.

Normal total leukocyte count but patient had lymphopenia.

Antidiphtheria Ab: 0.44 UI/mL (protection titer >1.0 UI/mL); peripheral blood mononuclear cell proliferation to PHA, PPD, and Candida were slightly reduced.

Normal levels of CD3+ and CD4+ but low levels of CD8+ (T cells), Low levels of B cells, NK cells and CD4+ (CD45RA+ and CD45RO+) cells. Normal levels of CD45RA+ but high levels of CD45RO+ (CD8 + T cells).

Born to nonconsanguineous parents.

CaseNotHPOs: N/A

CaseNotHPOFreeText: In 2013, the 45‐year‐old patient was admitted for sepsis. An elective total right hip replacement 6 months before had been followed by recurrent urosepsis. Postoperative diagnosis: recurrent urosepsis caused by Enteroccocus faecalis, Klebsiella pneumoniae and Pseudomonas aeruginosa.

For the next 3 years, the patient remained free of infection on IVIG replacement (0.6–0.8 g/kg) every 3–4 weeks, with a median IgG concentration of approximately 6 g/L. In October 2016, he underwent a transurethral resection of the prostate and soon afterward developed diarrhea and significant weight loss. He was again admitted to our hospital, but after extensive investigation, no infectious or immune‐mediated cause could be found. There was an excellent response to a short course of a higher dose of oral prednisolone (30 mg/day, tapered over the next 2 months to 5 mg/day). In February 2017, he was admitted to his local hospital with left‐sided epididymo‐orchitis and rapidly died from hospital‐acquired pneumonia.

CasePreviousTesting: Broad genetic screening using a custom panel of many immune‐related genes using an ion proton next‐generation sequencer, followed by Sanger sequencing, was performed at the Laboratory of Clinical and Infectious Diseases of the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. See Table 1.

GenotypingMethod: CTLA‐4 sequencing was performed after amplification of the four exons. See Table 1.

PreviouslyPublished: N/A

Variant: NM_005214.5:c.380A>G

ClinVarID: 949358

CAID: CA350138668

gnomAD: Not found

SupplementalData: N/A

Note: Not functionally tested using transendocytosis

• Title: Faster than expected

• subtitle: why most climate scientists can’t tell the truth (in public) Author: Jackson Damien

• This is a good article written from a psychotherapist's perspective,

• examining the psychology behind why published, mainstream, peer reviewed climate change research is always dangerously lagging behind current research,
• and recommending what interventions could be be taken to remedy this
• This your of scientific misinformation coming from scientists themselves
• gives minimizers and denialists the very ammunition they need to legitimise delay of the urgently needed system change.
• What climate scientists say In public is far from what they believe in private.
• For instance, many climate scientists don't believe 1.5 Deg. C target is plausible anymore, but don't say so in public.
• That reticence is due to fear of violating accepted scientific social norms,
• being labeled alarmist and risk losing their job.
• That creates a collective cognitive dissonance that acts as a feedback signal
• for society to implement change at a dangerously slow pace
• and to not spend the necessary resources to prepare for the harm already baked in.
• The result of this choice dissonance is that
• there is no collective sense of an emergency or a global wartime mobilisation scale of collective behaviour.
• Our actions are not commensurate to the permanent emergency state we are now in.
• The appropriate response that is suggested is for the entire climate science community to form a coalition that creates a new kind of peer reviewed publishing and reporting
• that publicly responds to the current and live knowledge that is being discovered every day.
• This is done from a planetary and permanent emergency perspective in order to eliminate the dangerous delays that create the wrong human collective behavioural responses.

Can't annotate on https://feedback.mailgun.com/forums/156243-feature-requests/suggestions/39905227-provide-meaningful-delivery-status-description-rat so posting here instead.

Anonymous commented · May 26, 2021 4:36 AM

Without your comment I'd never find the real issue, because I was only look at permanent failures. That error message is really misleading, hope they can fix this.

Kelly commented · December 30, 2020 2:35 AM

Yes we desperately need this too. Half of our recipients were soft bounced due to "Too old" but we could still send to them previously on other ESPs.

That could be a problem, if it actually send to the permanent failure hook in this case. Then you would have to hit their bounces API to check whether it's actually a permanent failure / hard bounce for the recipient as opposed to just for this message.

too old error

Exactly. I arrived at the same conclusion.

Just An Ordinary Bloke. (2022, January 6). But But But Sweden......... @afneil maybe Tegnall was wrong eh mate https://t.co/1S4SMWaqlU [Tweet]. @Unusual_Times. https://twitter.com/Unusual_Times/status/1479033464678723585

Nguyen, L. H., Drew, D. A., Graham, M. S., Joshi, A. D., Guo, C.-G., Ma, W., Mehta, R. S., Warner, E. T., Sikavi, D. R., Lo, C.-H., Kwon, S., Song, M., Mucci, L. A., Stampfer, M. J., Willett, W. C., Eliassen, A. H., Hart, J. E., Chavarro, J. E., Rich-Edwards, J. W., … Zhang, F. (2020). Risk of COVID-19 among front-line health-care workers and the general community: A prospective cohort study. The Lancet Public Health, 0(0). https://doi.org/10.1016/S2468-2667(20)30164-X

Socioeconomic Determinants of COVID-19 Infections and Mortality: Evidence from England and Wales. COVID-19 and the Labor Market. (n.d.). IZA – Institute of Labor Economics. Retrieved July 30, 2020, from https://covid-19.iza.org/publications/pp159/

Global public health data on COVID-19. (n.d.). Coronavirus (COVID-19): The Latest Science & Expert Commentary | Frontiers. Retrieved June 4, 2020, from https://coronavirus.frontiersin.org/covid-19-data-resources